The majority of the lymphocytes in the body are located in the gastrointestinal tract. A large percentage of these lymphocytes are activated CD4+ T cells and are prime targets for SIV/HIV persistence and replication. Intestinal lymphocytes and/or their cytokines are thought to play a major role in maintaining the structure and function of the intestinal mucosa. Alterations in the composition of GALT could induce physiologic changes in intestinal function and may be responsible for the syndrome known as AIDS enteropathy. To examine this hypotheses, we are examining morphologic and phenotypic changes in the intestinal tract of SIV-infected macaques. Ten rhesus monkeys were intravenously inoculated with SIVmac239 and sacrificed at 3, 7, 14, 21, and 50 days post-inoculation. Lymphocytes were isolated from peripheral lymph nodes, blood, spleen, and the epithelium and lamina propria of the jejunum, ileum, and colon, and analyzed by 4-color flow cytometry for CD2, 3, 4, 8, 20, 25, 28, 34, 38, 45RA, 56, Leu-8,_ TCR, and HLA-DR expression. Adjacent sections were analyzed for virus-infected cells by in situ hybridization. Within 14 days pi, profound drops in the proportion of CD4+ lymphocytes were observed in the intestine as compared to peripheral lymphoid tissues. Increased percentages of CD8+ cells with DR+38+ and CD56+CD38+ phenotypes were observed both in intestinal and peripheral lymphoid tissue by day 7 pi. In situ hybridization revealed that these changes correlated with peak viral load in the intestine. This data indicates that infection of the gastrointestinal tract with SIV results in marked changes in the proportions of intestinal lymphocyte subsets. Furthermore, changes in the GALT are far more pronounced than in peripheral lymphoid tissue. Finally, changes in intestinal lymphocyte subsets are most likely associated with marked alterations in intestinal function which could result in malabsorption, nutritional deficiencies, and/or increased susceptibility of the intestine to opportunistic infection.